Mono and bispyridinium oximes such as 2-PAM-Cl (pyridine 2-aldoxime methyl chloride) and toxogonin (N,N'-oxydimethylene bis(pyridinium 4-aldoxime) dichloride), serve as potent reactivators of acetylcholinesterase (AChE) inhibited by organophosphates. [F. Hobbiger, In Handbuch der Experimentellen Pharmakologie XII, Cholinesterases and Anticholinesterase Agents, Ed. G. B. Koelle, Springer Verlag, Berlin, p.921 (1963)].
The rational design of pyridinium oximes (Kewitz et al. archives Biochem. Biophys. 64, 456 (1956) as potential antidotes for treatment of organophosphorus poisoning indeed resulted in effective therapeutic agents against intoxication by a wide variety of insecticides and nerve agents. However, both 2-PAM-Cl and toxogonin (in combination with atropine) provide only partial protection against Soman (O-pinacolyl methylphosphonofluoridate) as well as other organophosphates causing rapid aging of organophosphonyl-AChE.
A new series of bis-pyridinium oximes HS-3, HS-6, HI-6, HGG-12 and HGG-42 first synthesized by Prof. Hagedorn and her collaborators (in Freiburg, Germany) were shown to be effective against respiratory failure and neuromuscular blockade caused by soman in rats and mice [O. L. Wolthuis and L. A. Kepener, Europ. J. Pharmacol. 49, 415 (1978)].
The therapeutic effect of the latter bispyridinium derivatives however, could not be entirely attributed to reactivation of phosphorylated AChE. Recently we demonstrated that several bispyridinium oximes bind specifically to the muscarinic receptor in mouse brain. The binding potency of these antidotes (K.sub.1 10.sup.-4 -10.sup.-5 M) was found to correlate well to the antimuscarinic efficiency in the guinea pig ileum assay [G. Amitai et al Biochem. Pharmacol. 29, 483 (1980)]. Pretreatment by a carbamate (e.g. pyridostigmine) followed by subsequent therapeutic application of cholinolytics (atropine and benactyzine) and an oxime reactivator(HS-6 or P2S) provided improved protection against soman (J. J. Gordon et al Toxicol. and Applied Pharmacol., 43, 207-216 (1978), J. Schenk et al. Arch. Toxicol. 36, 71-81 (1976).
The maximum protective ratio (P.R.)* against soman poisoning achieved by any presently available combined treatment regime is far from satisfactory. FNT *P.R.=(LD.sub.50 T)/(LD.sub.50) where LD.sub.50 T is the LD.sub.50 in animals that were administered antidotal treatment.